Integrated bioinformatic and in vivo analysis confirms the cardioprotective role of OPA1.

BACKGROUND: OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia/reperfusion injury. We sought to further assess OPA1 in cardiac pathologies, hypothesizing that OPA1 will function in a protective manner in chronic heart failure. METHODS: Integrated analyses of publicly available histological and transcriptomic data were used to identify functional associations between OPA1 and other genes of interest. To experimentally assess these associations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to a modified transverse aortic constriction surgery and underwent 2-dimensional and 4-dimensional echocardiography along with molecular analyses including high-resolution respirometry, enzymatic activities, flow cytometry and transcript level analyses. RESULTS: Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were associated with fatty acid, branch chain amino acid and cardiac contractile gene signatures. These functional associations were further supported by in vivo findings showing that OPA1-OE mice displayed improved 2D ejection fraction, end systolic volume, end diastolic volume and 4D cardiac functional parameters including global peak circumferential and surface area strain compared to WT mice. As well, OPA1-OE mice displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers and no induction of fibrotic transcript markers. CONCLUSION: These results further demonstrate the important role of OPA1 in supporting optimal cardiac function and highlight potentially protective contractile and metabolic signaling pathways.